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Haematology > 4. The haemoglobin molecule and thalassaemia > Flashcards

4. The haemoglobin molecule and thalassaemia Flashcards

1
Q

At which stages does Hb synthesis occur?

A

• Begins in pro-erythroblast:

  • 65% erythroblast stage
  • 35% reticulocyte stage
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2
Q

Where is haem synthesised?

A
  • In the mitochondria (which has the enzyme ALAS)

* Dependent upon Fe incorporation into the cell

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3
Q

Where is globin synthesised?

A

Cytoplasmic ribosomes

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4
Q

Which globin chains is HbA formed of?

A
  • 2α and 2β globin chains

* Each chain has a haem molecule at its centre

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5
Q

What is ferroprotoporphyrin?

A

Combination of protoporphyrin ring with central iron atom

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6
Q

How is globin synthesised?

A

• There are various different types of globin
• Combine with haem to form different haemoglobin molecules
• There are 8 functional globin chains arranged in 2 clusters:
- β-cluster (b, g, d and e globin genes) on the short arm of chromosome 11
- α-cluster (a and z globin genes) on the short arm of chromosome 16
• During early embryogenesis, production of cells in mainly in the yolk sac
• Later, the main sites of production are the liver and spleen
• Zeta and epsilon chains are produced until 6-8 weeks, after which there is a switch to alpha globin chains (problem - manifests early on, alpha thalassaemia major)
• Switch of production to bone marrow occurs shortly after birth

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7
Q

What are the 3 haemoglobins present in a normal adult?

A
  • HbA
  • HbA2
  • HbF
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8
Q

Which haemoglobin is present in sufficient quantity to be visible on a HPLC chromatogram?

A
  • Glycated HbA

* Only up to approx. 5%

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9
Q

Describe the primary, secondary and tertiary structure of globin

A
  • Primary - α-globin chains: 141aa, non-α-globin chains: 146aa
  • Secondary - 75% α and β form a helical arrangement
  • Tertiary - approximate sphere, hydrophilic surface (charged polar side chains), hydrophobic core, haem pocket
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10
Q

What does cooperativity refer to when talking about the O2 carrying capacity of Hb?

A

Binding of one molecule facilitates the second molecule binding

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11
Q

What is the P 50?

A

26.6mmHg

partial pressure of O2 at which Hb is half saturated with O2

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12
Q

What does the normal position of the oxygen-haemoglobin dissociation curve depend on?

A
  • Concentration of 2,3-DPG
  • H+ ion concentration (pH)
  • Concentration of CO2 in red blood cells
  • Structure of Hb
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13
Q

What can cause the oxygen-dissociation curve to shift right?

A 
Easy oxygen delivery (Hb only saturated at higher PO2, so gives up oxygen more easily)
• High 2,3-DPG
• High H+
• High CO2
• HbS
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14
Q

What can cause the oxygen-dissociation curve to shift left?

A

Gives up oxygen less readily (Hb saturated at lower PO2, increased affinity)
• Low 2,3-DPG
• HbF

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15
Q

What are haemoglobinopathies?

A
  • Genetic disorders characterised by a defect of globin chain synthesis
  • Most common inherited single gene disorder worldwide
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16
Q

How can we classify thalassaemia?

A
  • Look at the globin chain type affected

* Look at clinical severity (minor “trait”, intermedia, major)

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17
Q

How many genes have been identified on chromosome 16?

A
  • 7 genes identified (alpha like genes)
  • Only 3 expressed - ζ, α1, and α
  • 3 pseudo genes (ω) and a 4th gene that does not produce a detectable protein
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18
Q

Which genes have been identified on chromosome 11?

A
  • Beta like genes
  • ε and Gγ are expressed in the embryo
  • β and δ expressed during later development
  • The expression of δ globin chains never reaches that of the other globin chains
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19
Q

What is beta thalassaemia?

A
  • Deletion of mutation in β globin gene(s)
  • Results in reduced or absent production of β globin chains
  • Prevalence – mainly Mediterranean countries (Greece, Cyprus, Southern Italy), Middle-East, Africa, Southern China, South-East Asia
  • Inherited in recessive Mendelian fashion
  • Carriers are asymptomatic
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20
Q

What determines the severity of thalassaemia?

A
  • Degree of suppression of globin chain synthesis
  • Some mutations result in no globin production (β0)
  • Others have decreased levels of production (β+)
  • Inheritance of 2 β0 genes will give rise to a Major
  • Inheritance of 2 β+ genes will give rise to an intermedia (a clinically milder form)
21
Q

How can thalassaemia be diagnosed in the lab?

A

• Microcytic hypochromic blood picture in the absence of iron deficiency
• Relatively high RBC count compared to Hb
• Peripheral film shows target cells, poikilocytosis but no anisocytosis
• Beta: HbA2 is raised depending of severity (rarely >7%), and raised HbF
• No simple diagnostic process to diagnose alpha thalassaemia
- presumptive diagnosis can be made if microcytosis and hypochromia is seen in the absence of iron deficiency
• Globin chain synthesis/DNA studies - gold standard

22
Q

What are Globin Chain synthesis/DNA studies?

A
  • Gold standard
  • Genetic analysis for β-thalassaemia mutations and Xmnl polymorphism (in β-thalassaemias) and α-thalassaemia genotype (in all cases)
  • Can sequence the α globin gene
  • β-thalassaemia can usually be seen by electrophoresis
  • Blood film of beta thalassaemia trait will show microcytosis, hypochromia and occasional cells showing basophillic stippling
  • Marked degree of hypochromia due to Hb reduction in thalassaemia patients
  • Some degree of poikilocytosis, and we see target cell
23
Q

What causes thalassaemia major and what does it lead to?

A
  • Carry 2 abnormal copies of the beta globin gene (so no HbA can be made)
  • Leads to severe anaemia
  • Incompatible with life without regular blood transfusions
  • Clinical presentation usually after 4-6 months of life
24
Q

What does a peripheral blood film show?

A
  • Extreme hypochromia, microcytosis and poikilocytosis

* Howell-Jolly and nucleated RBCs often present (due to splenectophy and hyperplastic bone marrow)

25
Q

How many blood transfusions are needed for beta thalassaemia major?

A
  • 2-3 units per month

* Regular transfusion support

26
Q

What is the problem with regular blood transfusions and how is this overcome?

A
  • Iron overloaded

* Iron chelators to remove excess iron

27
Q

What are pappenheimer bodies and when are they seen?

A
  • Iron deposits
  • Result of long-term transfusion regimens
  • Seen as coarse blue granules in the RBCs (Perls stain)
28
Q

Apart from pappenheimer bodies, what other inclusion bodies can be seen in beta thalassaemia major?

A

Alpha globin precipitates

29
Q

What are the clinical presentations of thalassaemia major?

A

• Severe anaemia presenting after 4 months (beta)
• Hepatosplenomegaly
• Bone marrow will show erythroid hyperplasia
• Many of the consequences due to extra-medullar haematopoiesis
also e.g. prominence of maxilla bones and separation of the teeth

30
Q

What are the clinical features (and other possible complications) of beta thalassaemia?

A
  • Chronic fatigue
  • Failure to thrive
  • Jaundice
  • Delay in growth and puberty
  • Skeletal deformity
  • Splenomegaly
  • Iron overload (due to ineffective erythropoiesis)
  • Cholelithiasis and biliary sepsis
  • Cardiac failure
  • Endocripathies
  • Liver failure
31
Q

How can thalassaemia major be treated?

A
  • Regular blood transfusions
  • Iron chelations therapy
  • Splenectomy
  • Supportive medical care
  • Hormone therapy
  • Hydroxyurea to boost HbF
  • Bone marrow transplant - curative
32
Q

What infections are thalassaemia patients more susceptible to?

A
  • Yersinia - siderophilic (Fe loving) bacterium
  • Gram negative sepsis

(Splenectomised patients given prophylaxis)

33
Q

When do you start iron chelation therapy?

A
  • Years later or when serum ferritin >100mcg/l

* Audiology and opthalmology screening prior to starting

34
Q

How much of a difference has iron chelation therapy made to survival rates?

A
  • 1960s - survival of patients pass their 30s was <30%

* First drug in 70s/80s - survival of patients pass their 30s was 80%

35
Q

What are the 3 different types of iron chelators and how are they taken?

A
  • DFO - subcutaneous or IV infusion, 5 days a week, 8-12 hour infusion
  • Deferiprone - orally, 3 times a day, effective in reducing myocardial iron
  • Deferasirox - orally, once a day
36
Q

How can you increase the effectiveness of iron chelation in patients with heavy Fe overload?

A

Combination therapy

37
Q

What are the disadvantages of deferiprone?

A
  • Take it very often
  • Short plasma half life
  • Unpredictable control of body iron
  • Toxicity (e.g. zinc deficiency)
38
Q

What are the disadvantages of deferasirox?

A
  • Cardiac protection uncertain

* Toxicity (limited)

39
Q

How can iron overload be monitored?

A
  • Serum ferritin - >2500 associated with increased complications; check every 3 months if transfused, otherwise annually; acute phase protein, so can also increase in other situations
  • Liver biopsy - rare
  • T2 cardiac and hepatic (ferriscan) MRI to quantify [Fe] (e.g. <20ms relaxation of cardiac fibres suggestive of Fe deposition)
40
Q

How does a ferriscan determine liver iron concentration?

A
  • Normal liver [Fe] <3mg/g
  • > 15mg/g associated with sever complications
  • Check annually, or biannually if >20mg/g
41
Q

What does coinheritance of the sickle beta globin molecule with beta thalassaemia lead to

A
  • Sickling disorder, rather than a thalassaemia
  • Blood film shows features of both
  • HbS will be the dominant haemoglobin as little/no HbA
42
Q

What is HbE beta thalassaemia?

A
  • Common combination in South East Asia
  • Clinically variable in expression - can be as sever as beta thalassaemia major
  • Thalassaemia properties - reduction in globin chain production
43
Q

What is alpha thalassaemia (and cause)?

A
  • Deletion or mutation in alpha globin chain gene(s)
  • Reduced or absent production of alpha globin chains
  • Affects both feotus and adult as production starts early in embryogenesis
  • Excess β and γ chains form tetramers of HbH and Hb Barts respectively
  • Severity depends on number of globin genes affected - 4 in total
44
Q

What are the traits of a thalassaemia carrier

A
  • Carry a single abnormal copy of the beta globin gene (w.r.t. beta thalassaemia)
  • Carry either one or two abnormal copies of the alpha globin gene (w.r.t. alpha thalassaemia
  • Usually asymptomatic, usually diagnosed on the basis of mild anaemia
45
Q

Describe the peripheral blood film of HbH disease

A
  • Haemolytic element
  • Microcytosis, anisoocytosis, poikilocytosis
  • “Puddling” of haemoglobin within RBC
46
Q

What does Hb electrophoresis show in HbH disease?

A

A fast band

47
Q

What are the problems associated with treatment of thalassaemia in developing countries?

A
  • Lack of awareness of the problems
  • Lack of experience of health care providers
  • Availability of safe, screened blood
  • Cost and compliance with iron chelation therapy
  • Availability and cost of bone marrow transplant
48
Q

When should thalassaemia be screened for prevention/management?

A
  • Extended family screening
  • Pre-marital screening (compulsory in Cyprus)
  • Discourage marriage between realtives
  • Antenatal testing
  • Pre-natal diagnosis

Haematology (11 decks)

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